Natural killer (NK) cells are critical for host control of viral infections and tumorigenesis and are rapidly activated by pro-inflammatory cytokines such as interleukin (IL)-12, IL-18, and type I interferons. IL-12 and STAT4 signaling have also recently been shown to be required for the generation of virus-specific NK cell memory. These activating cytokines are thought to be counter-balanced by suppressive cytokines in order to regulate the effector response and prevent collateral damage. However, the exact role of suppressive cytokines, such as transforming growth factor (TGF)-, in controlling NK cell responses during viral infection or tumorigenesis is not yet known. Understanding the role of TGF- in suppressing the NK cell mediated immune response to tumor and virus will be critical in unleashing NK cells' full potential in future immunotherapies. To that end, this study will investigate the role of the immunosuppressive cytokine TGF- in NK cell function, particularly in the generation of effector and memory responses against viral infections and tumors. We have generated mice containing TGF--insensitive NK cells by crossing mice carrying floxed TGF- receptor II alleles (TGF-RIIfl/fl) to mice with the improved Cre-recombinase (iCre) inserted into the NKp46 gene locus (Nkp46iCre). We will compare the NK cell phenotype of these mice to that of wild-type controls directly, as well as in the bone marrow chimera and adoptive transfer settings. For viral studies, we will use the mouse cytomegalovirus (MCMV) infection model that is well established in our lab. This is a particularly important model because human cytomegalovirus (HCMV) causes life-threatening complications in immunosuppressed patients such as those undergoing chemotherapy or bone marrow transplantation. For tumor studies, we will use the B16 melanoma model, which is known to be susceptible to NK cell lysis. Through this investigation we hope to elucidate the role of TGF- in regulating the NK cell effector response and how this role could potentially be manipulated to improve NK cell mediated immunity.